scholarly journals Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

2019 ◽  
Author(s):  
Guang Shi ◽  
D. Thirumalai
Keyword(s):  
Cell Population ◽  
Genome Organization ◽  
Large Cell ◽  
Spatial Distance ◽  
Chromosome Organization ◽  
Conformational Heterogeneity ◽  
Interphase Chromosome ◽  
Length Scales ◽  
Rouse Model ◽  
Contact Probability

AbstractHi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Contact probability should decrease as the spatial distance between two loci increases. However, studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci, with larger Hi-C readout, is paradoxically larger compared to another pair with a smaller value of the contact probability. Here, we show that the FISH-Hi-C paradox can be resolved using a theory based on a Generalized Rouse Model for Chromosomes (GRMC). The FISH-Hi-C paradox arises because the cell population is highly heterogeneous, which means that a given contact is present in only a fraction of cells. Insights from the GRMC is used to construct a theory, without any adjustable parameters, to extract the distribution of subpopulations from the FISH data, which quantitatively reproduces the Hi-C data. Our results show that heterogeneity is pervasive in genome organization at all length scales, reflecting large cell-to-cell variations.

scholarly journals Erythrocytes 3D genome organization in vertebrates

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anastasia Ryzhkova ◽  
Alena Taskina ◽  
Anna Khabarova ◽  
Veniamin Fishman ◽  
Nariman Battulin
Keyword(s):  
Blood Cells ◽  
Genome Organization ◽  
Large Scale ◽  
Chromatin Condensation ◽  
Erythroid Differentiation ◽  
Interaction Patterns ◽  
3D Interaction ◽  
Interphase Chromosome ◽  
3D Genome ◽  
Contact Maps

AbstractGeneration of mature red blood cells, consisting mainly of hemoglobin, is a remarkable example of coordinated action of various signaling networks. Chromatin condensation is an essential step for terminal erythroid differentiation and subsequent nuclear expulsion in mammals. Here, we profiled 3D genome organization in the blood cells from ten species belonging to different vertebrate classes. Our analysis of contact maps revealed a striking absence of such 3D interaction patterns as loops or TADs in blood cells of all analyzed representatives. We also detect large-scale chromatin rearrangements in blood cells from mammals, birds, reptiles and amphibians: their contact maps display strong second diagonal pattern, representing an increased frequency of long-range contacts, unrelated to TADs or compartments. This pattern is completely atypical for interphase chromosome structure. We confirm that these principles of genome organization are conservative in vertebrate erythroid cells.

scholarly journals Temporal changes of lysosome and phagosome pH during phagolysosome formation in macrophages: studies by fluorescence spectroscopy.

1981 ◽  
Vol 89 (3) ◽  
pp. 645-652 ◽  
Author(s):  
M J Geisow ◽  
P D'Arcy Hart ◽  
M R Young
Keyword(s):  
Fluorescence Spectroscopy ◽  
Cell Population ◽  
External Medium ◽  
Large Cell ◽  
Peritoneal Macrophages ◽  
Ph Change ◽  
Ph Changes ◽  
Indicator Dyes ◽  
Kinetics Of ◽  
Mouse Peritoneal Macrophages

Intravascular pH was measured within the lysosomes and newly formed phagosomes in cultured mouse peritoneal macrophages. The kinetics of pH change in both vacuolar systems was quantitatively determined within a large cell population by fluorescence spectroscopy. Additionally, pH changes within individual phagosomes were followed semiquantitatively using indicator dyes. Two novel findings were made. Firstly, the pH in new phagosomes was transiently driven alkaline (higher than physiological) even when the external medium was buffered at pH 6.5. Secondly, perturbations of phagosome-lysosome fusion had little effect upon phagosomal pH changes, even though the compounds used markedly altered the pH of the lysosomes in resting and phagocytosing cells.

scholarly journals Topologically associated domains enriched for lineage-specific genes reveal expression-dependent nuclear topologies during myogenesis

2016 ◽  
Vol 113 (12) ◽  
pp. E1691-E1700 ◽  
Author(s):  
Daniel S. Neems ◽  
Arturo G. Garza-Gongora ◽  
Erica D. Smith ◽  
Steven T. Kosak
Keyword(s):  
Gene Regulation ◽  
Genome Organization ◽  
Spatial Organization ◽  
Potential Role ◽  
Spatial Distance ◽  
Linear Distribution ◽  
Myotube Formation ◽  
Topologically Associated Domains ◽  
The Relationship ◽  
Lineage Specific Genes

The linear distribution of genes across chromosomes and the spatial localization of genes within the nucleus are related to their transcriptional regulation. The mechanistic consequences of linear gene order, and how it may relate to the functional output of genome organization, remain to be fully resolved, however. Here we tested the relationship between linear and 3D organization of gene regulation during myogenesis. Our analysis has identified a subset of topologically associated domains (TADs) that are significantly enriched for muscle-specific genes. These lineage-enriched TADs demonstrate an expression-dependent pattern of nuclear organization that influences the positioning of adjacent nonenriched TADs. Therefore, lineage-enriched TADs inform cell-specific genome organization during myogenesis. The reduction of allelic spatial distance of one of these domains, which contains Myogenin, correlates with reduced transcriptional variability, identifying a potential role for lineage-specific nuclear topology. Using a fusion-based strategy to decouple mitosis and myotube formation, we demonstrate that the cell-specific topology of syncytial nuclei is dependent on cell division. We propose that the effects of linear and spatial organization of gene loci on gene regulation are linked through TAD architecture, and that mitosis is critical for establishing nuclear topologies during cellular differentiation.

scholarly journals Resolution of DNA damage at the single-cell level shows largely different actions of X-rays and bleomycin.

1995 ◽  
Vol 43 (2) ◽  
pp. 229-235 ◽  
Author(s):  
M I Affentranger ◽  
W Burkart
Keyword(s):  
Single Cell ◽  
Cell Population ◽  
Large Cell ◽  
Dna Strand Breaks ◽  
Single Cell Level ◽  
X Rays ◽  
Cell Level ◽  
Strand Breaks ◽  
Two Agents ◽  
Dna Strand

Both X-rays and the radiomimetic agent bleomycin (BLM) induce DNA strand breaks, predominantly via reactive radicals. To compare the induction of breaks with the two agents in Chinese hamster (CHO-K1) cells, two different alkaline unwinding methods, a 3H tracer-based analysis of large cell populations and an optical adaption allowing measurement of single cells, were applied. Radiation and BLM show qualitatively similar dose responses when the average number of DNA strand breaks is measured in a large cell population. However, the breakage pattern at the single-cell level indicates large discrepancies between the actions of the two agents. Irradiated cells show a uniform distribution of DNA strand breaks over the cell population. Effects of treatment with 30 micrograms x ml-1 BLM for 2 hr vary from practically zero in some cells to high levels of DNA strand breakage in others. Unlike the repair of radiation-induced DNA breaks, the repair efficiency of BLM-induced DNA strand breaks, as measured at the single-cell level, varies strongly among cells of the same population. Such heterogeneity at the cellular level potentially reduces BLM's usefulness for tumor therapy because the appearance of BLM-resistant subpopulations may critically impair treatment outcome.

scholarly journals Allele Frequency Spectrum in a Cancer Cell Population

2017 ◽  
Author(s):  
H. Ohtsuki ◽  
H. Innan
Keyword(s):  
Population Genetics ◽  
Cell Division ◽  
Allele Frequency ◽  
Frequency Spectrum ◽  
Cancer Cell ◽  
Cell Population ◽  
Large Cell ◽  
Parental Cancer ◽  
Allele Frequency Spectrum ◽  
Cancer Cell Population

ABSTRACTA cancer grows from a single cell, thereby constituting a large cell population. In this work, we are interested in how mutations accumulate in a cancer cell population. We provided a theoretical framework of the stochastic process in a cancer cell population and obtained near exact expressions of allele frequency spectrum or AFS (only continuous approximation is involved) from both forward and backward treatments under a simple setting; all cells undergo cell division and die at constant rates, b and d, respectively, such that the entire population grows exponentially. This setting means that once a parental cancer cell is established, in the following growth phase, all mutations are assumed to have no effect on b or d (i.e., neutral or passengers). Our theoretical results show that the difference from organismal population genetics is mainly in the coalescent time scale, and the mutation rate is defined per cell division, not per time unit (e.g., generation). Except for these two factors, the basic logic are very similar between organismal and cancer population genetics, indicating that a number of well established theories of organismal population genetics could be translated to cancer population genetics with simple modifications.

scholarly journals The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH)

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 734-736 ◽  
Author(s):  
David J. Araten ◽  
Lucio Luzzatto
Keyword(s):  
Cell Division ◽  
Cell Population ◽  
Mutation Rate ◽  
Genetic Instability ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Somatic Mutations ◽  
Intrinsic Rate ◽  
Large Cell ◽  
Normal Range ◽  
Hematopoietic System

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations (μ) in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, μ ranged from 1.24 × 10–7 to 11.2 × 10–7, against a normal range of 2.4 × 10–7 to 29.6 × 10–7 mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.

scholarly journals Significance of the inital cytomorphological and immunocytochemical findings and the correlation with the international prognostic index for the survival in patients with non-Hodgkin’s lymphoma

2006 ◽  
Vol 63 (1) ◽  
pp. 31-36
Author(s):  
Biljana Mihaljevic ◽  
Ruzica Nedeljkov-Jancic ◽  
Vesna Cemerikic-Martinovic
Keyword(s):  
Cell Population ◽  
Fine Needle Aspiration ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Large Cell ◽  
Needle Aspiration ◽  
Small Cells ◽  
Mixed Cell ◽  
Fine Needle ◽  
Mixed Cell Population

Background/Aim. Fine-needle aspiration biopsy is a quick, economical, and safe initial method in managing a patient with suspected lymphoma. According to a few reports on this preoblem, the aim of this study was to compare histological findings to cytomorphological ones in needle aspirates. We also compared these findings to the overal survival (OS) time. Methods. We analyzed the fine-needle aspiration biopsies of peripheral lymph nodes, and the International Prognostic Index (IPI) in 81 patients with non-Hodgkin?s lymphoma (NHL). We put these findings into correlation with OS time. Results. According to the International Working Formulation (IWF) criteria, the dominant cell population was as follows: 18 patients had the small cell population, 21 patients had small cleaved cells, 18 patients had the mixed cell population, 21 patients had large cell population, 2 patients had Burkitt lymphoma type, and 1 patient had the dominant lymphoblasts. On presentation, 32 patients had a low IPI index, 32 patients had a low intermediate, and 17 patients had a high intermediate IPI. We confirmed the statistical significance (Kaplan-Mayer) of cytomorphology (p = 0.013) and IPI index (p = 0.016) for survival time. During a 48-month follow-up, OS was 37.2 months for the patients with the dominant small cells, and 32 months for the patients with small cleaved cells (PH equivalent to indolent NHL). For the patients with the dominant mixed cell population, large cell population and Burkitt limphoma cell, OS were 17, 14.4, and 9.3 months, respectively (PH equivalent to aggressive NHL). Patients with low IPI had the highest OS, 36 months for the low intermediate and only 11.6 months for the high intermediate IPI index. Conclusion. We concluded that an initial cytological and clinical profile of patients with NHL, might give a quick and relevant information for planning an adequate therapy.

scholarly journals Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries

2021 ◽  
Author(s):  
Omid Gholamalamdari ◽  
Liguo Zhang ◽  
Yu Chen ◽  
Andrew Belmont
Keyword(s):  
Genome Organization ◽  
Large Scale ◽  
Chromatin Domain ◽  
Interphase Chromosome ◽  
Chromatin Domains ◽  
Nuclear Compartment ◽  
Chromatin Compaction ◽  
Domain Boundaries ◽  
Chromatin Remodeling Complexes ◽  
Local Enrichment

AbstractLarge-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.

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